ITK is a non-receptor type tyrosine kinase belonging to the Tec family and essential for the activation of T cells, and is mainly expressed in T cells, mast cells and natural killer cells. ITK is activated in T cells upon stimulation of T cell receptor (TCR), and is activated in mast cells upon activation of high-affinity immunoglobulin (Ig) E receptor. Subsequent to the receptor stimulation in T cells, Lck, which is one member of the Src tyrosine kinase family, phosphorylates Y511 in the ITK kinase domain activation loop. The activated ITK is, together with Zap-70, necessary for the phosphorylation and activation of PLC-γ. PLC-γ catalyzes formation of inositol 1,4,5-trisphosphoric acid and diacylglycerol, causing calcium mobilization and PKC activation, respectively. These events activate many down stream pathways, and finally cause cytokine production in T cells and degranulation in mast cells.
Studies using ITK knockout mouse have confirmed that ITK is involved in the differentiation of Th2 cells.
Th2 cell is one kind of CD4 positive helper T cells (Th cells), which differentiates from naive T cells by antigen stimulation, and produces cytokine. Cytokines such as interleukin (IL)-4, IL-5, IL-13 and the like produced by Th2 cells are called Th2 cytokine and are known to be involved in the mechanism of allergic disease and the like, since it promotes antibody production by plasma cells differentiated from B cells and activates cells such as eosinophils (one kind of granulocytes) and the like. Like Th2 cell, Th1 cell that differentiates from naive T cells produces so-called Th1 cytokines such as interferon (IFN)-γ and the like, and Th1 cell and Th2 cell maintain an equilibrium relation called Th1/Th2 balance by suppressing functions of each other. An imbalance toward either cytokine is considered to cause diseases specific to each of them. ITK knockout mouse has been reported to selectively inhibit Th2 cell differentiation and Th2 cytokine production.
Moreover, it has been reported that ITK inhibition inhibits activation of mast cells.
Mast cell contains various chemical mediators such as histamine. When an antigen is bound to IgE bound to the cell surface, the established crosslinking triggers cell activation, which consequently causes release of its content (chemical mediators such as histamine and the like) (degranulation). Of the chemical mediators released from the mast cells, histamine and the like have a bronchial smooth muscle constriction action, a blood vessel permeability enhancing effect, a mucous secretory action and the like and cause asthma and allergic diseases.
Therefore, an ITK inhibitor that suppresses growth of Th2 cell and production of Th2 cytokine, and/or suppresses degranulation and production of histamine and the like by suppression of activation of mast cells is expected to show effect as an agent for the treatment or prophylaxis of the diseases involving growth of Th2 cell, production of Th2 cytokine, degranulation, production of histamine and the like, for example, inflammatory diseases, allergic diseases and the like.
Recently, ITK is suggested to be also involved in the activation of Th17 cell, which is one kind of Th cells, and an ITK inhibitor is expected to show effect as an agent for the treatment or prophylaxis of the diseases involving Th17 cell, such as autoimmune diseases (e.g., rheumatism and the like).
In addition, ITK is suggested to be involved in a mixed-lymphocyte reaction. Thus, an ITK inhibitor is expected to show effect as an inhibitor of rejection in transplantation.
Furthermore, ITK is suggested to be involved in HIV infection. Thus, an ITK inhibitor is expected to show effect as a prophylactic or therapeutic agent for HIV infection.